EP0699672B1 - Process for preparing benzoic acid derivative intermediates and benzothiophene pharmaceutical agents - Google Patents

Process for preparing benzoic acid derivative intermediates and benzothiophene pharmaceutical agents Download PDF

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Publication number
EP0699672B1
EP0699672B1 EP95306050A EP95306050A EP0699672B1 EP 0699672 B1 EP0699672 B1 EP 0699672B1 EP 95306050 A EP95306050 A EP 95306050A EP 95306050 A EP95306050 A EP 95306050A EP 0699672 B1 EP0699672 B1 EP 0699672B1
Authority
EP
European Patent Office
Prior art keywords
formula
alkyl
reaction product
compound
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP95306050A
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German (de)
English (en)
French (fr)
Other versions
EP0699672A1 (en
Inventor
Douglas Patton Kjell
Fred Mason Perry
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
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Eli Lilly and Co
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Publication date
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Publication of EP0699672A1 publication Critical patent/EP0699672A1/en
Application granted granted Critical
Publication of EP0699672B1 publication Critical patent/EP0699672B1/en
Anticipated expiration legal-status Critical
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the fields of pharmaceutical and organic chemistry and provides novel processes for preparing compounds of formula I wherein
  • compounds of formula I are prepared by reacting, for example, ⁇ -chloroethylpiperidine hydrochloride and ethyl 4-hydroxybenzoate in methyl ethyl ketone, in the presence of potassium carbonate ( see , U.S. Pat. No. 4,418,068.)
  • the referenced synthetic route has certain undesirable aspects. Firstly, the solvent, methyl ethyl ketone, is hazardous and requires expensive handling and disposal procedures. Secondly, use of this solvent sets a limit of 80° C as a reaction temperature during formation of an ester, thus limiting the rate of the potassium carbonate catalyzed alkylation reaction. Furthermore, the organic layer containing the ester must be stripped to an oil prior to dissolution of the oil in aqueous sodium hydroxide and methanol. This oil preparation step is time consuming and could reduce the ultimate yield with large-scale production.
  • the present invention provides a novel process for preparing compounds of formula I wherein
  • the present invention further provides a process for preparing compounds of formula II wherein
  • One aspect of the present invention provides a process for preparing a compound of formula I wherein
  • C 1 -C 4 alkyl refers to straight or branched chains of 1 to 4 carbon atoms including, methyl, ethyl, propyl, isopropyl, butyl, n-butyl, and isobutyl; and the term “C 1 -C 6 alkyl” encompasses the groups included in the definition of "C 1 -C 4 alkyl” in addition to groups such as pentyl, isopentyl, hexyl, isohexyl, and the like.
  • halo includes bromo, chloro, fluoro, and iodo.
  • R 3 and R 4 hydroxy protecting groups when R 3 and R 4 are not H, denote groups which generally are not found in final, therapeutically active compounds, but which are intentionally introduced during a portion of the synthetic process to protect a group which otherwise might react in the course of chemical manipulations, and is then removed at a later stage of the synthesis. Since compounds bearing such protecting groups are of importance primarily as chemical intermediates (although some derivatives also exhibit biological activity), their precise structure is not critical.
  • hydroxy protecting groups include, for example -C 1 -C 4 alkyl, -CO-(C 1 -C 6 alkyl), -SO 2 -(C 4 -C 6 alkyl), and -CO-Ar in which Ar is optionally substituted phenyl.
  • substituted phenyl refers to a phenyl group having one or more substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 5 alkoxy, hydroxy, nitro, chloro, fluoro, and tri(chloro or fluoro) methyl.
  • C 1 -C 5 alkoxy represents a C 1 -C 5 alkyl group attached through an oxygen bridge such as, for example, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
  • Preferred R 3 and R4 hydroxy protecting groups are C 1 -C 4 alkyl, particularly methyl.
  • a preferred formula III compound is that in which R 1 and R 2 combine to form piperidinyl, n is 2, and X is chloro, while a preferred formula IV compound is that in which R is ethyl.
  • Appropriate acetate solvents include those in which the alkyl moiety of such solvent is a straight or branched chain alkyl moiety having one to nine carbon atoms.
  • the preferred solvent is amyl acetate because it is environmentally friendly, is inexpensive, and has a high boiling point which allows the alkylation to take place at relatively high temperatures.
  • Other appropriate acetate solvents include, for example, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isoamyl acetate, and the like.
  • acetate solvents used in the present process have distinct advantages over the prior art ketone solvents such as methyl ethyl ketone. Acetate solvents are much safer than ketone solvents and require less expensive handling and disposal procedures. Equally important, acetate solvents allow the present process to be run at a higher temperature than the temperature which may be used with ketone solvents. Thus, the reaction can be run at a faster, more economical rate, and the reaction can be more complete, particularly when used for large scale production.
  • the present process obviates the need for stripping the organic layer containing a formula I compound to an oil prior to cleaving the terminal ester for reaction in the below-described process.
  • an alkyl acetate solvent In addition to an alkyl acetate solvent, the present process, as well as the process described below, is run in the presence of an appropriate base.
  • Appropriate bases include organic and inorganic bases, but inorganic bases, particularly a carbonate or bicarbonate base, is preferred. Of these, powdered potassium carbonate is especially preferred. Although the presence of a base is necessary for the present process to run, powdered potassium carbonate is the most efficient for enhancing the speed of the reaction.
  • alkylation reaction mixture under an inert atmosphere, such as, for example, argon, or, particularly, nitrogen.
  • the present reaction may be run at a temperature from about 80° C to the reflux temperature of the solvent.
  • a preferred temperature range is from about 100° C to about 150° C, while a range from about 115° C to about 120° C is especially preferred.
  • the length of time for this reaction is that amount necessary for the reaction to occur. Typically, this reaction takes from about 2 to about 24 hours.
  • the optimal time can be determined by monitoring the progress of the reaction via conventional chromatographic techniques.
  • the alkylation mixture typically is cooled, to about 30° C to about 70° C, and washed with water to dissolve the added basic salt.
  • An appropriate aqueous acid is then added to the mixture to extract a compound of formula Ia wherein
  • aqueous hydrochloric acid is used for the extraction process, forming a hydrochloride salt of the formula I compound.
  • Other aqueous acids such as, for example, sulfuric acid, phosphoric acid, acetic acid and the like, may be used, and the corresponding formula I acid salt is provided.
  • the alkyl ester of the desired formula Ia compound is then cleaved via standard procedures, providing a compound of formula I.
  • the formula I acid extract is heated to a temperature in the range from about 80° C to about 150° C, preferably from about 95° C to about 100° C.
  • an acceptable level of formula I compound is produced in about 4 hours. Continued heating for up to 24 hours will not affect either quality or yield.
  • the ester cleaving may be accelerated by distilling and removing the alcohol formed via acid hydrolysis.
  • Isolation and purification of the formula I acid is accomplished using procedures well known to one of ordinary skill in the art. Generally, the resulting mixture from the ester cleavage step is cooled to a temperature range from about -5° C to about 20° C. Although the product will crystallize or precipitate out of solution at this range, the optimum temperature range is from about 0° C to about 5° C. The desired formula I compound is then isolated by filtration.
  • Another aspect of the invention provides a process for preparing a compound of formula II wherein
  • steps a), b), and c) are the same as steps a), b), and c) in the above described process, plus additional step d) (acylation of a formula V compound with a formula I compound), step e) (optional removal of any hydroxy protecting group), and step f) (optional salt formation of a protected or deprotected compound of formula II).
  • step d) the reaction product from step c) which, preferably, is isolated and purified prior to the initiation of this step, is reacted with a compound of formula V wherein R 3 and R 4 are as defined above.
  • a 124 g portion of the above intermediate was added in small portions to 930 g of polyphosphoric acid at 85°C. The temperature rose to 95° C, during the addition, and the mixture was stirred at 90° C for 30 minutes after the addition was complete, and was then stirred an additional 45 minutes while it cooled without external heating.
  • One liter of crushed ice was then added to the mixture, and the external ice bath was applied to control the temperature while the ice melted and diluted the acid. 500 hundred mL of additional water was added, and the light pink precipitate was filtered off and washed, first with water and then with methanol.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Nutrition Science (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Cephalosporin Compounds (AREA)
  • Furan Compounds (AREA)
EP95306050A 1994-08-31 1995-08-30 Process for preparing benzoic acid derivative intermediates and benzothiophene pharmaceutical agents Expired - Lifetime EP0699672B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US298636 1994-08-31
US08/298,636 US5631369A (en) 1994-08-31 1994-08-31 Process for preparing benzoic acid derivative intermediates and benzothiophene pharmaceutical agents

Publications (2)

Publication Number Publication Date
EP0699672A1 EP0699672A1 (en) 1996-03-06
EP0699672B1 true EP0699672B1 (en) 1998-04-22

Family

ID=23151367

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95306050A Expired - Lifetime EP0699672B1 (en) 1994-08-31 1995-08-30 Process for preparing benzoic acid derivative intermediates and benzothiophene pharmaceutical agents

Country Status (17)

Country Link
US (2) US5631369A (fi)
EP (1) EP0699672B1 (fi)
JP (1) JPH08119964A (fi)
KR (1) KR100359959B1 (fi)
AT (1) ATE165355T1 (fi)
BR (1) BR9503846A (fi)
CA (1) CA2157236A1 (fi)
CY (1) CY2092B1 (fi)
DE (1) DE69502152T2 (fi)
DK (1) DK0699672T3 (fi)
ES (1) ES2114721T3 (fi)
FI (1) FI114706B (fi)
GR (1) GR3026742T3 (fi)
HK (1) HK1006912A1 (fi)
HU (2) HU222121B1 (fi)
IL (1) IL115092A0 (fi)
TW (1) TW427975B (fi)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL333356A1 (en) * 1996-08-28 1999-12-06 Lilly Co Eli Amorphous benzothiophenes, methods of obtaining them and ways of their application
CA2231013A1 (en) * 1997-04-30 1998-10-30 Eli Lilly And Company Process for preparing benzoic acid derivative intermediates and benzothiophene pharmaceuticals
US7124425B1 (en) * 1999-03-08 2006-10-17 Immersion Entertainment, L.L.C. Audio/video system and method utilizing a head mounted apparatus with noise attenuation
WO2001023369A2 (en) * 1999-09-27 2001-04-05 Eli Lilly And Company Process for preparing benzoic acids
FR2817865B1 (fr) * 2000-12-11 2005-02-18 Sanofi Synthelabo Derive aminoalkoxybenzoyle sous forme de sel, son procede de preparation et son utilisation comme intermediaire de synthese
EP1546138B1 (en) 2002-09-30 2012-01-18 A/S GEA Farmaceutisk Fabrik Raloxifene l-lactate or a hemihydrate thereof, their uses, pharmaceutical compositions and preparation processes
US7012153B2 (en) * 2003-12-22 2006-03-14 Eli Lilly And Company Process for preparing benzoic acids
IN2014MN00380A (fi) 2006-06-30 2015-06-19 Iceutica Pty Ltd
CA2759125C (en) 2009-04-24 2017-08-15 Iceutica Pty Ltd A novel formulation of indomethacin
US9526734B2 (en) 2014-06-09 2016-12-27 Iceutica Pty Ltd. Formulation of meloxicam
KR102117214B1 (ko) 2020-03-26 2020-06-01 유지씨 주식회사 에어 리스 스프레이 건 용 도료 비산 방지 커버 하우징
KR102145873B1 (ko) 2020-06-10 2020-08-20 유지씨 주식회사 에어 리스 스프레이건 용 도료 비산 방지 커버 하우징 및 그 비산 방지 커버 하우징이 결합 된 고소작업대용 도색장치 및 그 비산 방지 커버 하우징이 결합 된 달비계용 도색 장치 및 그 비산 방지 커버 하우징이 결합 된 평면용 도색장치
KR102227020B1 (ko) 2020-12-18 2021-03-12 유지씨 주식회사 스프레이 건 용 도료 비산 방지 커버 하우징 결합체
KR102444617B1 (ko) 2021-05-28 2022-09-16 이다지 도장용 스프레이건의 비산방지장치
KR102607000B1 (ko) 2023-03-24 2023-11-29 이다지 도장용 스프레이 건의 비산방지장치

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3947470A (en) * 1974-06-20 1976-03-30 Smithkline Corporation Substituted benzofurans and benzothiophenes
US4133814A (en) * 1975-10-28 1979-01-09 Eli Lilly And Company 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents
US4358593A (en) * 1981-04-03 1982-11-09 Eli Lilly And Company Process for preparing 3-(4-aminoethoxybenzoyl)benzo[b]thiophenes
IL65379A0 (en) * 1981-04-03 1982-05-31 Lilly Co Eli Process for preparing acylated benzothiophenes
US4418068A (en) * 1981-04-03 1983-11-29 Eli Lilly And Company Antiestrogenic and antiandrugenic benzothiophenes
GB2097788B (en) * 1981-04-03 1985-04-24 Lilly Co Eli Benzothiophene compounds and process for preparing them
US4380635A (en) * 1981-04-03 1983-04-19 Eli Lilly And Company Synthesis of acylated benzothiophenes
US4656187A (en) * 1981-08-03 1987-04-07 Eli Lilly And Company Treatment of mammary cancer
CA2020887A1 (en) * 1989-07-28 1991-01-29 Michael Klaus Aromatic carboxylic amides

Also Published As

Publication number Publication date
HK1006912A1 (en) 1999-03-19
CA2157236A1 (en) 1996-03-01
FI114706B (fi) 2004-12-15
US5631369A (en) 1997-05-20
US5750688A (en) 1998-05-12
BR9503846A (pt) 1996-09-17
KR960007543A (ko) 1996-03-22
FI954067A (fi) 1996-03-01
ES2114721T3 (es) 1998-06-01
DK0699672T3 (da) 1998-10-07
FI954067A0 (fi) 1995-08-30
TW427975B (en) 2001-04-01
EP0699672A1 (en) 1996-03-06
CY2092B1 (en) 2002-04-05
HU222121B1 (hu) 2003-04-28
DE69502152T2 (de) 1998-09-17
KR100359959B1 (ko) 2003-01-14
HU0003473D0 (fi) 1995-08-30
ATE165355T1 (de) 1998-05-15
GR3026742T3 (en) 1998-07-31
DE69502152D1 (de) 1998-05-28
IL115092A0 (en) 1995-12-08
HU9502537D0 (en) 1995-10-30
HUT73141A (en) 1996-06-28
JPH08119964A (ja) 1996-05-14

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